Metabolic Alterations in Aorta Induces Brain Cholesterolemia, Memory Loss and Cognitive Dysfunction in Diabetic Mice

AIM: Diabetic hyperlipidemia and associated cognitive dysfunction are of major concern and is essential to understand the mechanism and pathophysiology of diabetic brains, which remains unknown. In this study, we investigated whether hypercholesterolemia induces apoptosis and cognitive dysfunction, in diabetic apolipoprotein E (APOE) and paraoxonase 1 (PON1) double knockout (DKO) mice brains. HYPOTHESIS: We hypothesize that hypercholesterolemia induces apoptosis that involves cognitive dysfunction and furthers to Alzheimer's. METHODS: ApoE-PON1 DKO mice (6±2 months) were divided into control and STZ groups. At Day-28, brain function, blood glucose, and serum lipids were measured followed by subjecting animals to Glucose Tolerance Test. Echocardiography was performed, and mice aortas were isolated. Brain-parameters were examined using RT-PCR, immunohistochemistry, and histologically. RESULTS: We observed a significant (p<0.05) increase in blood glucose levels, serum lipids, increased aortic lesions, as well as increased cholesterol loading and apoptotic markers in brains of diabetic mice as compared to control. A significant reduction in reverse cholesterol transport, and HDL-associated proteins were observed. A significant (p<0.05) decrease in brain weight, size, and brain function were observed in diabetic mice. Furthermore, a significant (p<0.05) increase in PTEN and decrease in AKT levels were observed in diabetic mice. In addition, a significant (p<0.05) increase in Alzheimer's specific markers were also observed. CONCLUSION: In conclusion, our data suggest that hyperlipidemia induces apoptosis, that leads to neuronal cell death, memory-loss, and cognitive dysfunction, which furthers Alzheimer's in diabetic ApoE and PON1 DKO mice. Further therapeutic approaches require to be developed to target hyperlipidemia in diabetic brains. © FASEB.